TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma

August 1, 2019

For IC50 measurement using the FGFR inhibitors, cells were dissociated into single cells and seeded into a 384-well tissue culture plate, each well with 200 viable cells and 40 ÎźL of growth medium. After 24 hours, compounds were added to each well over a 15-point concentration range, along with DMSO controls, using a Tecan D300e digital drug dispenser. Cells were cultured for 5 days in the presence of compound before assessing viability by adding 15 ÎźL of CellTiterGlo (Promega) to each well, incubating for 20 minutes at room temperature on a shaker, and measuring luminescence using an Envision

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983. Š2019 American Association for Cancer Research.

Goyal, L; Shi, L; Liu, LY; Fece de la Cruz, F; Lennerz, JK; Raghavan, S; Leschiner, I; Elagina, L; Siravegna, G; Ng, RWS; Vu, P; Patra, KC; Saha, SK; Uppot, RN; Arellano, R; Reyes, S; Sagara, T; Otsuki, S; Nadres, B; Shahzade, HA; Dey-Guha, I; Fetter, IJ; Baiev, I; Van Seventer, EE; Murphy, JE; Ferrone, CR; Tanabe, KK; Deshpande, V; Harding, JJ; Yaeger, R; Kelley, RK; Bardelli, A; Iafrate, AJ; Hahn, WC; Benes, CH; Ting, DT; Hirai, H; Getz, G; Juric, D; Zhu, AX; Corcoran, RB; Bardeesy, N;

Journal: Cancer Discov Pages: 1064-1079

Original article (31109923)